Published online before print April 6, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2007.060975v1 170/6/2112    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sossey-Alaoui, K. Articles by Cowell, J. K. Search for Related Content PubMed Articles by Sossey-Alaoui, K. Articles by Cowell, J. K.

(American Journal of Pathology. 2007;170:2112-2121.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060975

Down-Regulation of WAVE3, a Metastasis Promoter Gene, Inhibits Invasion and Metastasis of Breast Cancer Cells

Khalid Sossey-Alaoui^*, Alfiya Safina^*, Xiurong Li^*, Mary M. Vaughan, David G. Hicks, Andrei V. Bakin^* and John K. Cowell^*

From the Departments of Cancer Genetics^* and Pathology, Roswell Park Cancer Institute, Buffalo, New York

The expression of WAVE3, an actin-cytoskeleton and reorganization protein, is elevated in malignant human breast cancer, yet the role of WAVE3 in promoting tumor progression remains undefined. We have recently shown that knockdown of WAVE3 expression in human breast adenocarcinoma MDA-MB-231 cells using small interfering RNA resulted in a significant reduction of cell motility, migration, and invasion, which correlated with a reduction in the levels of active p38 mitogen-activated protein kinase. Here, we investigated the effect of stable suppression of WAVE3 by short hairpin RNA on tumor growth and metastasis in xenograft models. Breast cancer MDA-MB-231 cells expressing short hairpin RNA to WAVE3 (shWAVE3) showed a significant reduction in Matrigel invasion and formation of lung colonies after tail-vein injection in SCID mice. In the orthotopic model, we observed a reduction in growth rate of the primary tumors, as well as in the metastases to the lungs. We also show that suppression of p38 mitogen-activated protein kinase activity by dominant-negative p38 results in comparable phenotypes to the knockdown of WAVE3. These studies provide direct evidence that the WAVE3-p38 pathway contributes to breast cancer progression and metastasis.

This article has been cited by other articles:

				K. Sossey-Alaoui, X. Li, and J. K. Cowell c-Abl-mediated Phosphorylation of WAVE3 Is Required for Lamellipodia Formation and Cell Migration J. Biol. Chem., September 7, 2007; 282(36): 26257 - 26265. [Abstract] [Full Text] [PDF]